The objective of this program is to refine and develop new techniques and methods of electron microscopy and apply them to observations on biomolecular materials, ultimately at a level that can be used to delineate primary structure of specifically labelled nucleic acids. The techniques and methods to be developed include use of crystalline substrates, and special phase contrast and dark field imaging to enhance the signal from the biomolecular object and reduce substrate noise. During development, these methods will be applied to investigations on the quaternary structure of biologically significant enzymes and the tertiary and secondary structure of their protein subunits and nucleic acids. An experimental high resolution electron microscope developed under a separate program will be used for the investigations at ultimate levels of resolution.